Do We Need New HCV Drugs? YES - PDF Free Download

Do We Need New HCV Drugs? YES Nancy Reau, MD Professor of Medicine Chief, Section of Hepatology Associate Director, Solid Organ Transplantation Rush University Medical Center

Disclosures Consultation: AbbVie, Abbott, Merck, Gilead, BMS Research (paid to Rush): AbbVie, Abbott, Shire, Intercept, GenFit 2

HCV Projected To Be A Rare Disease By 236 Estimated HCV prevalence in the US from 21-25 Our study underscores the need for more aggressive screening strategies to reduce the burden of HCV infection. Why develop drugs for a disease that s been cured? Ann Intern Med. 214;161:17-18

Incidence of Acute HCV in the US: Incidence per 1, population 1992-25 3 2,5 2 1,5 1,5 1992 1996 2 24 28 212 MMWR. 215;62(53):1-122.

Incidence of Acute HCV in the US: Incidence per 1, population 1992-213 3 2,5 2 1,5 1,5 1992 1996 2 24 28 212 MMWR. 215;62(53):1-122.

Pts Using Drugs/Alcohol Denied Access to HCV Treatment in Some Settings Medicaid reimbursement criteria for DAAs based on required drug/alcohol abstinence period Greenwald R, et al. CHLPI/NVHR Summary Report. 216.

Pts With Minimal Liver Disease Denied HCV Treatment Access in Many Settings Medicaid reimbursement criteria for DAAs based on documented liver fibrosis stage required for reimbursement Greenwald R, et al. CHLPI/NVHR Summary Report. 216.

History and Evolving Landscape of HCV Therapy Why develop drugs if the current therapy works? Discovery of HCV (Chiron) HCV Antibody Testing Approval Ribavirin Approval pegifnalfa-2b Genotype-Specific RGT Approval Telaprevir Boceprevir Approval Ledipasvir/Sofosbuvir OBV/PTV-R + DAS Approval Simeprevir Sofosbuvir Approval Daclatasvir Approval Grazoprevir/Elbasvir Sofosbuvir/Velpatasvir 1989 1992 1998 21 25 211 213 214 215 216 *Novel alloral & pangenotypic regimens SVR: 6% 12% 2% 4% 54% 65 75% > 9% pegifn-alfa 2b = peg-interferon alfa-2b; RGT = response-guided therapy; OBV/PTV-R + DAS = ombitasvir/paritaprevir and ritonavir + dasabuvir (or 3D). Houghton M. Liver Int. 29;29(Suppl 1):82-88; Carithers RL, et al. Hepatology. 1997;26(3 Suppl 1):S83-S88; Zeuzem S, et al. N Engl J Med. 2;343(23): 1666-1672; Poynard T, et al. Lancet. 1998;352(9138):1426-1432; McHutchison JG, et al. N Engl J Med. 1998;339(21):1485-1492; Lindsay KL, et al. Hepatology. 21;34(2):395-43; Fried MW, et al. N Engl J Med. 22;347(13):975-982; Manns MP, et al. Lancet. 21;58(9286):958-965; Poordad F, et al. N Engl J Med. 211;364(13):1195-126; Jacobson IM, et al. N Engl J Med. 211;364(25):245-2416; Lawitz E, et al. N Engl J Med. 213;368(2):1878-1887; Jacobson IM, et al. Lancet. 214;384(9941):43-413; Afdhal N, et al. N Engl J Med. 214;37(2):1889-1898; Nelson DR, et al. Hepatology. 215;61(4):1127-1135; Zeusem S, et al. Ann Intern Med. 215;163(1):1-13; Feld JJ, et al. N Engl J Med. 215;373(27):2599-267.; Foster GR, et al. N Engl J Med. 215;373(27):268-2617.

Does Difficult To Treat Still Exist? Historic First wave DAA 2nd Wave DAA Future? Age >65 BMI HIV HIV DDIs Black Renal failure Cirrhosis Cirrhosis Decompensated Decompensated Treatment experienced High viral load TE HVL IL28B TT Post-OLT RAV DAA failure Genotype 1 Genotype 3 ACCESS

Traditional Factors Have Lost Impact Baseline Characteristics on SVR: PrOD ± RBV P value P value HCV GT1a <.1 Fibrosis Stage NS Weight.7 Cirrhosis NS Hispanic /Latino Ethnicity.13 Albumin NS IL28B TT Genotype.34 Platelet Count NS HCV RNA.41 Treatment Experienced Treatment Regimen (3D + RBV) NS NS Treatment Duration NS IL28B CT Genotype NS History of Diabetes NS Age Sex Multivariate Stepwise Regression Analysis of Baseline Factors of All Treated Patients NS NS History of Depression /Bipolar Disorder History of Bleeding Disorders Race NS Former Injection Drug Use NS BMI NS Geographic Region NS NS NS Multivariate Stepwise Regression Analysis of Baseline Factors for Label-recommended Regimen Odds Ratio P value BMI.874.1 HCV GT1a.66.8 =1% 1= 98% 2= 95% 11/12 431/436 721/743 596/626 16/123 9/11 1964 /241 Negative predictors: HCV GT1a, weight 75kg, IL28B TT, Hispanic/Latino, HCV RNA 8, IU/mL Reau N, et al. 5th EASL; Vienna, Austria; April 22-26, 215. Abst. P781.

1. Not Everyone can be cured Difficult To Treat Historic First wave DAA 2 nd Wave DAA Future Age >65 BMI HIV HIV DDIs Black Renal failure Cirrhosis Cirrhosis Decompensated Decompensated Treatment experienced High viral load TE HVL IL28B TT Post-OLT RAV DAA failure Genotype 1 Genotype 3 Genotype 3 +RAS ACCESS

Rare- but how do we re-treat patients who fail DAAs? Summary of Phase 3 studies of IFN-free therapy in GT 1 patients published NEJM 214* 4% Trial ION-1 ION-2 ION-3 SAPPHIRE-I SAPPHIRE-II PEARL-III PEARL-IV TURQUOISE-II Regimen LDV/SOF ± RBV LDV/SOF ± RBV LDV/SOF ± RBV OMV/PTV/RTV + DSV + RBV OMV/PTV/RTV + DSV + RBV OMV/PTV/RTV + DSV + RBV OMV/PTV/RTV + DSV + RBV OMV/PTV/RTV + DSV + RBV 368/ 3826 SVR Liang J, Ghany MG. N Engl J Med 214;37:243 7 *Included treatment-naïve and -experienced patients ± cirrhosis.

SVR12 (%) RAS -> Some could Respond to Current Therapy LDV/SOF x 24 Weeks After Failing 8-12 weeks LDV/SOF 1 1 69 1 1 8 8 5 8 33 6 6 4 4 2 2 11/11 11/16 7/14 None 1 2 5/5 Q3R or M28T* 4/5 L31M 2/6 Y93H/N Number of NS5A RAV(s) Type of Single NS5A RAV *M28T (n=1). Lawitz E, et al. EASL 215. Abstract O5.

The POLARIS Phase 3 Program SOF/VEL/VOX N=263 POLARIS-1 GT 1-6 NS5A TE 41% cirrhosis Wk Wk 12 SOF/VEL/VOX N=51 POLARIS-2 GT 1-6 DAA TN 18% Cirrhosis (no 3) Wk Wk 8 Wk 12 SOF/VEL /VOX N=11 POLARIS-3 GT 3 DAA TN 1% Cirrhosis Wk Wk 8 SOF/VEL/VOX SOF/VEL/VOX Wk 12 Wk N=182 POLARIS-4 GT 1,2,3,4 DAA TE (no NS5A) 46% Cirrhosis SOF/VEL/VOS Wk 12 n=152 Placebo N=44 SOF/VEL N=19 SOF/VEL N=151 SOF/VEL SVR 96% vs. % SVR 95% vs. 98% SVR 96% vs. 95% SVR 97% vs. 9% Zeuzem et al. 19 Oral AASLD 216 Bourliere et al.194 Oral AASLD 216 3-4% Failure 14

SVR12, % POLARIS-1 and -4: Impact of Baseline RASs on 12-wk SOF/VEL/VOX in DAA-experienced Pts Baseline RASs: None Any NS3 only NS5A only NS3 + NS5A 1 98 99 1 1 97 1 1 1 1 1 99 94 94 1 1 97 97 97 98 1 1 8 6 4 2 n/n = 41 /4 2 173/ 175 45/ 45 59 /5 9 69/ 71 8/ 8 23/ 23 3/ 3 23/ 23 3/ 3 69/ 7 Genotype 5/ 53 1 2 3 4-6 1 2 3 4 47/ 5 2/ 2 9/ 9 36/ 37 31/ 32 144/ 148 89/ 91 33/ 33 16/ 16 Number of RASs Slide credit: clinicaloptions.com Sarrazin, et al. EASL 217. Abstract THU-248.

SVR12 (%) MAGELLAN-1: GLE/PIB in GT1 or 4 HCV With Previous DAA Failure Of pts with both NS3 and NS5a RASs, 9/9 had previous failure with PI + NS5A 5/9 had SVR12 on GLE/PIB 12-wk GLE/PIB 16-wk GLE/PIB 1 8 1 88 79 1 94 81 1 1 83 1 1 96 6 4 2 n/n = 14/ 14 PI Only 14/ 16 NS5A Only 11/ 14 PI + NS5A 13/ 13 PI Only 17/ 18 NS5A Only 13/ 16 PI + NS5A 13/ 13 None 2/ 2 NS3 Only 2/ 24 NS5A Only 13/ 13 None 4/ 4 NS3 Only 22/ 23 NS5A Only Previous DAA Therapy Baseline RAS Slide credit: clinicaloptions.com Poordad F, et al. EASL 217. Abstract PS-156.

How Do We Treat 2 nd Generation Failures? RAS testing might not identify high risk patients G/P failures had complicated resistance patterns that current salvage might not cover 4% 3-2%?5% SVR SVR SVR? 17

There is more to difficult than TE Recommended Therapies for Patients with Renal Impairment Severity Creatinine Clearance Therapy Genotype Mild to Moderate 3 8 ml / min LDV/SOF SOF/VEL PrOD GZP/EBV Severe or ESRD <3 ml/min GZP/EBV PrOD Peg-IFN + RBV 1, 4 6 1 6 1, 4 1, 4 1, 4 1 2, 3, 5, 6 Do investigational therapies show promise for patients with severe renal impairment?

Expedition-4 Glecaprevir/Pibrentasvir HCV GT 1-6 Patients with Renal Impairment Key Inclusion Criteria: HCV GT 1 6 CKD 4 5 ±cirrhosis TN or TE* Study Design Treatme nt Period G/P N = 14 Follow- Up Period SVR12 12 24 36 SVR12: Intent-to-Treat Analysis 1 75 5 25 98 12 14 IIT Analysis 88% of patients had CKD Stage 5 and 82% were on hemodialysis * TE defined as IFN/pegIFN ± RBV or SOF + RBV ± pegifn therapies TN = treatment naïve; TE = treatment experienced Gane E, et al. AASLD 216. Boston, MA. Abstract #LB-11.

There is more to difficult than TE Recommended Therapies for Patients with Renal Impairment Severity Creatinine Clearance Therapy Genotype Mild to Moderate 3 8 ml / min LDV/SOF SOF/VEL GZP/EBV G/P Severe or ESRD <3 ml/min GZP/EBV PrOD G/P Peg-IFN + RBV 1, 4 6 1 6 1.4 1-6 1, 4 1 1-6 What about ESRD+decompensated cirrhosis http://www.hcvguidelines.org/full-report/unique-patient-populations-patients-renal-impairment

Difficult To Treat Historic First wave DAA 2 nd Wave DAA Future Age >65 BMI HIV HIV DDIs Black Renal failure Cirrhosis Cirrhosis Decompensated Decompensated Treatment experienced High viral load TE HVL IL28B TT Post-OLT RAV DAA failure Genotype 1 Genotype 3 Genotype 3 +RAV ACCESS

Bigger Fish To Fry 22

2. New Population Needs New Treaters Next wave of chronic HCV PWID/OST MSM Underinsured Marginal Medical Literacy HCV therapy will move to the medical home 24

Strategies to Optimize Therapy Simplify the regimen Decrease toxicity Shorten duration Improve efficacy

Strategies to Optimize Therapy Simplify the regimen Decrease toxicity Shorten duration Improve efficacy This is where drug development is concentrating

1. Expand Provider Pool 2. Lesson Paperwork 3. Eliminate Thought Ultra-SHORT SIMPLE Simple Independent of patient and viral characteristics Rules Rules Rules Cirrhosis Genotype Sub Genotype Viral Load RAS DDIs

3. Confidence to be Cost Effective Shortening therapy lowers price 29

Clinical Question Does 8 weeks of LDV/SOF achieve SVR rates equal to ION-3? Are US providers using this therapy for TN, G1, non-cirrhotic with HCV PCR < 6 millions? 3

Guidelines: Is 8 Weeks An Option? AASLD Treatment Naïve, Non-cirrhotic Done at the discretion of the practitioner Not Recommended HIV-infected patients African-American patients, IL28B polymorphism CT or TT. EASL Treatment can be shortened to 8 weeks in treatmentnai ve patients without cirrhosis if their baseline HCV RNA level is below 6 million (6.8 Log) IU/ml. This should be done with caution in patients with F3 fibrosis (B1). EASL Recommendations on Treatment of Hepatitis C 216. J Hepatol (216), http://dx.doi.org/1.116/j. jhep.216.9.1 www.hcvguidelines.org assessed 3/23/217 31

SVR12 (%) LDV/SOF 8 weeks- Kowdley DDW 216 SVR12 in ION-3 Compared to Real-World Cohorts GT 1: LDV/SOF 8 weeks 1 97 93 98 98 99 92 98 97 97 99 8 6 4 2 119/ 123 ION-3 1138/ 1227 Veterans Affairs 631/ 644 DHCR 331/ 338 Burman's pharmacy 271/ 275 TRIO Cohort 238/ 258 Kaiser Permanente Northern California 236/ 24 Kaiser Permanente Los Angeles 155/ 159 GECCO 15/ 154 HCV Target 127/ 128 ifi Kowdley. ION-3. NEJM * Backus, VA, Hepatology 216 *** Terrault. HCV-TARGET. AASLD 215 ** Afdhal. TRIO. LBP-519 *** EASL 16 ** Buggisch. IFI. SAT-243 *** Curry. GECCO. AASLD 215 *** Latt. Kaiser. SAT-227 ** Buggisch. DHC-R. SAT-241 *** Qureshi. Burman s. SAT-192 ** Lai. Kaiser. SAT-177 *** Real-World Data across >3, patients treated with LDV/SOF 8 weeks achieved high and comparable SVR to LDV/SOF 12 weeks *Post hoc analysis ** Per Protocol *** ITT analysis ; patients were primarily treatment-naive non-cirrhotic patients with BL viral load < 6 million IU/mL 3 2

Real-World Efficacy of LDV/SOF ± RBV: HCV-TARGET N (%) Treatment Status Naïve Experienced DAA Experienced HCV GT1 Patients (N = 1,27) 674 (53) 596 (47) 167 (13) Cirrhosis 479 (38) Decompensated 17 (13) Liver Transplant 129 (1) HIV 39 (3) 1% 75% 5% 25% % 97% 97% 95% 97% 92% 15/ 154 LDV/SOF 67/ 627 8 wks 12 wks 24 wks 12 wks 24 wks SVR12 153/ 161 Relapse LDV/SOF + RBV 86/ 89 12/ 13 87% of G1, TN NC with HCV RNA <6 million IU/ ml; 35% received an 8-wk regimen -> 8-wk regimen is underutilized Terrault N, et al. AASLD 215; San Francisco, CA. Abstract 94.

4. Competition: Access and Price The economic impact of competition Competition affects market outcomes More competition, more players, more dynamic entry and exit, and more intense rivalry for customers tend to deliver better market outcomes Outcomes include lower prices and better access to services for consumers http://www.eldis.org/go/home&id=5571&type=document#.wt2u91kzpk 34

Medicine is a unique market Prices can not be easily discounted once a product comes to market Drug development may be the only way to impact price until a generic is produced The consumer is not the entity who uses the drug Pricing is not transparent Each new agent upsets the balance 35

Conclusions 1. Despite a cure, HCV is here to stay 2. Not all patients can be cured 3. New treaters entering work force need simple rules 4. Pricing still limits access which limits eradication 37